title: A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis.
abstract: Fabry disease is a lysosomal storage disorder in which neutral glycosphingolipids, predominantly Gb3 (globotriaosylceramide), accumulate due to deficient α-Gal A (α-galactosidase A) activity. The GLAko (α-Gal A-knockout) mouse has been used as a model for Fabry disease, but it does not have any symptomatic abnormalities. In the present study, we generated a symptomatic mouse model (G3Stg/GLAko) by cross-breeding GLAko mice with transgenic mice expressing human Gb3 synthase. G3Stg/GLAko mice had high Gb3 levels in major organs, and their serum Gb3 level at 5-25 weeks of age was 6-10-fold higher than that in GLAko mice of the same age. G3Stg/GLAko mice showed progressive renal impairment, with albuminuria at 3 weeks of age, decreased urine osmolality at 5 weeks, polyuria at 10 weeks and increased blood urea nitrogen at 15 weeks. The urine volume and urinary albumin concentration were significantly reduced in the G3Stg/GLAko mice when human recombinant α-Gal A was administered intravenously. These data suggest that Gb3 accumulation is a primary pathogenic factor in the symptomatic phenotype of G3Stg/GLAko mice, and that this mouse line is suitable for studying the pathogenesis of Fabry disease and for preclinical studies of candidate therapies.
authors.affiliation: *Department of Matrix Medicine, Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Taguchi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Maruyama
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nameta
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Junichiro
authors.initials: J
authors.lastname: Matsuda
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Yoshioka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D014281:Trihexosylceramides / Q000096:biosynthesis* / Q000235:genetics; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D014281:Trihexosylceramides; C018549:globotriaosylceramide; D005700:Galactosyltransferases; C045097:UDP-galactose-lactosylceramide alpha 1-4-galactosyltransferase; D000519:alpha-Galactosidase